Buffered compositions for dialysis

ABSTRACT

Acid concentrates, and dialysate compositions prepared therefrom, contain citric acid and an effective amount of a buffering agent selected from acetate and/or lactate. The buffering agent allows a physiologically acceptable amount of citrate to maintain the desired pH of the dialysate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/606,150, filed Jun. 24, 2003 (now allowed); which is acontinuation-in-part of U.S. patent application Ser. No. 09/421,622,filed Oct. 19, 1999 (now U.S. Pat. No. 6,610,206, issued Aug. 26, 2003);which application claims the benefit of U.S. Provisional PatentApplication No. 60/105,049, filed Oct. 20, 1998, which applications areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to therapeutic compositions, andparticularly to dialysate compositions.

2. Description of the Related Art

When functioning correctly, the kidneys help the body maintain a normalinternal environment called homeostasis. Kidneys help accomplish thisnormal balance by ridding the body of excess fluids and metabolic wasteproducts (toxins) as well as maintaining precise levels of glucose andelectrolytes. Kidney failure can be caused by multiple factors. However,regardless of why a person's kidneys fail, the failure results in theaccumulation of excess fluid and toxic waste in that person's body. Thisuremic poisoning eventually causes death unless the waste material isremoved by some artificial means. Hemodialysis is the most commontherapeutic measure for a person whose kidneys no longer perform theirblood purifying function. Another common type of dialysis is peritonealdialysis (PD).

Dialysate is the fluid utilized in dialysis, where dialysate serves to‘clean’ the blood of kidney failure patients. During hemodialysis, thepatient's blood is circulated on one side of a membrane within adialyzer (i.e., artificial kidney), while dialysate flows on the otherside of the membrane. Since blood and dialysate are separated by asemipermeable membrane, movement of molecules can occur between theblood and dialysate. Although the membrane pores are too small to permitblood cells and proteins to leave the blood, the pores allow wasteproducts to be transferred from the blood to the dialysate.

Peritoneal dialysis utilizes the patient's peritoneal membrane as adialysis membrane. Upon instilling a volume of peritoneal dialysate intothe peritoneal cavity, osmotic pressure and a diffusion gradient causeexcess fluid and waste products to leave the blood by crossing theperitoneal membrane and accumulate in the peritoneal cavity containingthe dialysis fluid. After a sufficient dwell time, the spent peritonealdialysate together with the accumulated excess fluid and waste productsare drained from the peritoneal cavity.

Today, virtually all dialysate for hemodialysis is made at the site oftreatment (in a hemodialysis machine) by mixing (1) treated water, (2)an acid concentrate, and (3) a base concentrate. Because the baseconcentrate typically contains sodium bicarbonate as the primary basicmaterial, dialysate made by mixing these ingredients is commonly knownas bicarbonate dialysate. Bicarbonate dialysate is almost universallymade in the hemodialysis machine, through the use of a “three-stream”proportionate pumping mechanism wherein the treated water, liquid ‘acidconcentrate’ and liquid bicarbonate (base) concentrate are combined. Onepatient typically requires 120 liters or more of dialysate for a singlehemodialysis treatment. Chronic kidney failure patients are treated 3times per week, 52 weeks per year.

The concentrates are supplied to the dialysis clinic in two forms; the‘acid concentrate’ is generally supplied as a liquid and the bicarbonateis shipped as a dry powder. The acid concentrate typically containssodium chloride, calcium chloride, potassium chloride, magnesiumchloride, dextrose and sufficient acid (acetic acid) for pH balance. Theprecise composition of the acid concentrate to be used in a specificdialysis session is determined by a doctor's prescription.

Prior to a patient's treatment session, a jug of liquid acid concentrateis obtained. Generally, this jug of concentrate is drawn from a largertank or drum of the acid concentrate. A staff member of the dialysisclinic also prepares a jug of sodium bicarbonate concentrate by mixing aquantity of powdered sodium bicarbonate with a specific quantity oftreated water. Separate concentrated solutions of ‘acid’ and bicarbonateare necessary because combining concentrated acid and base solutionswould cause the precipitation of calcium and magnesium carbonates. Afterproper mixing, the final dialysate has the concentrations prescribed bythe physician.

As noted, kidney failure patients accumulate excess fluids and normallyexcreted substances in their blood, most notably, blood urea nitrogen(BUN) and creatinine. In fact, the reduction in the blood levels ofthese two substances is generally used to gauge the efficiency andoverall effectiveness of dialysis. Often the efficiency of dialysis canbe compromised by a number of factors, one of which could be theblockage of dialyzer membrane pores by clotted blood.

Additionally, many kidney failure patients suffer from chronic acidosisbecause their kidneys are not able to remove acid. Traditionally, one ofthe several goals of hemodialysis treatment is the correction ofacidosis by providing higher than normal amounts of bicarbonate in thedialysate to buffer the excess acid in the blood. However, despiteinfusing “extra” bicarbonate during hemodialysis, normal bloodbicarbonate levels are not sustained in many patients betweenhemodialysis treatments.

Accordingly, there is a need in the art for improved dialysateformulations that increase the efficiency of the hemodialysis treatment.The present invention is directed to meeting this need and providesadditional related advantages as disclosed herein.

BRIEF SUMMARY OF THE INVENTION

The present invention provides compositions, termed dialysate precursorcompositions, which may be diluted with water and mixed with a base tothereby form a dialysate composition. The dialysate precursorcomposition, as well as the dialysate compositions prepared therefrom,contain citric acid and an effective amount of a buffering agentselected from acetate and/or lactate. The buffering agent requires aphysiologically acceptable amount of citrate to maintain the desired pHof the dialysate.

In one embodiment, the invention provides a dialysate precursorcomposition. This composition contains, at a minimum, water; chloride ata concentration ranging from about 1,000 to about 7,000 mEq/L; citrateat a concentration ranging from about 20 to about 900 mEq/L, at leastone buffering anion selected from acetate and/or lactate at aconcentration ranging from about 0.01 to about 150 mEq/L; and at leastone physiologically-acceptable cation. In a related embodiment, theinvention provides a dry dialysate precursor composition which, uponmixing with water, provides an aqueous composition having theabove-recited components in the above-recited concentrations. In oneembodiment the dry dialysate precursor composition is a pellet ortablet, while in another embodiment the dry dialysate precursorcomposition is a powder.

In another embodiment, the invention provides a dialysate composition.This dialysate composition contains, at a minimum, treated water;chloride at a concentration ranging from about 20 to about 200 mEq/L;citrate at a concentration ranging from about 0.5 to about 30 mEq/L; atleast one buffering anion selected from acetate and/or lactate at aconcentration ranging from about 0.01 to about 4.5 mEq/L; base includingbicarbonate; and at least one physiologically-acceptable cation. In arelated embodiment, the invention provides a dry dialysate compositionwhich, upon mixing with water, provides an aqueous composition havingthe above-recited components in the above-recited concentrations. In oneembodiment the dry dialysate composition is a pellet or tablet, while inanother embodiment the dry dialysate composition is a powder.

In another embodiment, the present invention provides a method offorming a dialysate precursor composition. The method includes the stepof mixing together treated water, chloride, citrate, at least onebuffering anion selected from acetate and/or lactate, and at least onephysiologically-acceptable cation to provide a composition havingchloride at a concentration ranging from about 1,000 to about 7,000mEq/L, citrate at a concentration ranging from about 20 to about 900mEq/L, and at least one buffering anion selected from acetate andlactate at a concentration ranging from about 0.01 to about 150 mEq/L.In a related embodiment, the invention provides a method of forming adialysate precursor composition which includes the step of mixing waterwith a dry dialysate precursor composition comprising the above-recitedcomponents, so as to provide an aqueous composition having theabove-recited component concentrations. In one embodiment, the drydialysate precursor composition is a pellet or tablet, while in anotherembodiment the dry dialysate precursor composition is a powder.

In another embodiment, the present invention provides a method offorming a dialysate composition. The method includes the step of mixingthe dialysate precursor composition with an aqueousbicarbonate-containing solution. The dialysate precursor compositioncontains, at a minimum, treated water, chloride, citrate, at least onebuffering anion selected from acetate and lactate, and at least onephysiologically-acceptable cation to provide a concentrate havingchloride at a concentration ranging from about 44 to about 143 mEq/L,citrate at a concentration ranging from about 1.5 to about 30 mEq/L, andat least one buffering anion selected from acetate and lactate at aconcentration ranging from about 0.01 to about 3.6 mEq/L.

In other embodiments, the present invention provides compositionsprepared according to the afore-described methods.

In another embodiment, the present invention provides an aqueousacid-concentrate composition which contains water, chloride at aconcentration of about 1,000 to about 7,000 mEq/L; citrate at aconcentration ranging from about 20 to about 900 mEq/L; and sufficientphysiologically-acceptable cations to provide for a neutral composition.This acid-concentrate composition has a pH of less than 4, and does notcontain any of acetate, bicarbonate or lactate.

In a related embodiment, the invention provides a dry acid-concentrateprecursor composition comprising the above-recited components (absentthe water) which, upon mixing with water, provides the aqueousacid-concentrate composition having the indicated components in theindicated concentrations. In one embodiment, the dry acid-concentrateprecursor composition is a pellet or tablet, while in another embodimentthe dry acid-concentrate precursor composition is a powder.

The magnesium concentration is preferably less than or equal to 2 mEq/L,and the calcium concentration is preferably less than or equal to 4.5mEq/L, and the bicarbonate concentration is preferably within the rangeof 25-40 mEq/L. The calcium and magnesium concentrations should beadjusted to higher values as the amount of citrate in the compositionincreases, in order to compensate for citrate's binding to serum calciumand/or magnesium.

In another embodiment, the present invention provides sterilecompositions specifically suited for peritoneal dialysis. According toone embodiment, the invention provides a peritoneal dialysatecomposition comprising treated water, citrate at a concentration ofabout 0.5-30 mEq/L; chloride at a concentration of about 20-200 mEq/L;bicarbonate at a concentration of about 5-100 mEq/L assuming allcarbonate-containing species are in the bicarbonate form, glucose at aconcentration of about 10-100 g/L; and a sufficient number ofphysiologically-acceptable cations to neutralize all of the citrate,chloride, bicarbonate, and any other anionic species that may be presentin the composition. In another embodiment, the invention provides acomposition for peritoneal dialysis as described above, but without anywater. This embodiment thus provides a dry composition, to which sterilewater may be added in order to form a peritoneal dialysate.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a plot of Dialysate pH (y-axis) vs. Sodium AcetateConcentration (x-axis), and shows the effect on pH of adding sodiumacetate to dialysate when the bicarbonate concentrate solution had aninitial pH of 8.14.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides compositions, termeddialysate precursor compositions, which contain, or are prepared from,components including water, chloride, citrate, at least one bufferinganion preferably selected from acetate and/or lactate, and at least onephysiologically-acceptable cation. The dialysate precursor composition,upon mixing with a base and with dilution, forms a biocompatiblecomposition that can be used for either hemodialysis or peritonealdialysis. In a related aspect, the invention provides a dry dialysateprecursor composition which, upon mixing with water, provides an aqueouscomposition having the above-recited components. In one embodiment thedry dialysate precursor composition is a pellet or tablet, while inanother embodiment the dry dialysate precursor composition is a powder.

As discussed in more detail below, the presence of some buffering anion,e.g., an anion selected from acetate and/or lactate, in the dialysateprecursor composition allows the dialysate precursor composition to beused as the acid concentrate in a standard three-stream dialysismachine, along with standard base (i.e., bicarbonate) concentrate,thereby mitigating problems associated with fluctuations in the pH ofthe dialysate during a dialysis treatment. Absent the buffering anion,the dialysate can have pH and/or conductivity properties which areoutside the ranges considered acceptable by health care professionals.Prior to a more extended discussion of the compositions of theinvention, and the properties thereof, the primary ingredients of thecompositions will be described.

As used herein, “chloride” refers to anionic chloride. Thus, the term“chloride” includes anionic chloride and the salt forms thereof, such asmay be formed from chloride anion(s) and physiologically-acceptablecation(s). The term “chloride” is not intended to include compoundswherein the chloride atom is covalently bonded to, for example, a carbonatom in an organic molecule. Exemplary physiologically-acceptablecations include, without limitation, hydrogen ions (i.e., protons),metal cations, and ammonium cations. Metal cations are generallypreferred, where suitable metal cations include, but are not limited to,the cationic forms of sodium, potassium, magnesium and calcium. Ofthese, sodium and potassium are preferred, and sodium is more preferred.When iron or trace element is desirably included in the composition, themetal cation may be iron cation (i.e., ferric or ferrous cation) or maybe a cation of a trace element, e.g., selenium or zinc cation. Acomposition containing chloride salts may contain a mixture ofphysiologically-acceptable cations.

In one embodiment, the chloride in the precursor dialysate compositionis present at a concentration ranging from about 1,000 to about 7,000mEq/L, preferably from about 2,000 to about 5,000 mEq/L. In general, theconcentrations of the components of present precursor dialysatecomposition are individually prescribed by a physician to reduce,increase, or normalize the concentrations of various components of thepatient's blood, plasma, or serum. Accordingly, the preciseconcentration of chloride in the precursor dialysate composition, andthe dialysate composition prepared therefrom, will be determined by aphysician according to principles known in the art.

As used herein, “citrate” refers to a citrate anion, in any form,including citric acid (citrate anion complexed with three protons),salts containing citrate anion, and partial esters of citrate anion.Citrate anion is an organic, tricarboxylate with the following chemicalformula:

Citric acid, which has been assigned Chemical Abstracts Registry No.77-92-2, has the molecular formula HOC(CO₂H)(CH₂CO₂H)₂ and a formulaweight of 192.12 g/mol. A citrate salt (i.e., a salt containing citrateanion) is composed of one or more citrate anions in association with oneor more physiologically-acceptable cations. Exemplaryphysiologically-acceptable cations include, but are not limited to,protons, ammonium cations and metal cations. Suitable metal cationsinclude, but are not limited to, sodium, potassium, calcium, andmagnesium, where sodium and potassium are preferred, and sodium is morepreferred. A composition containing citrate anion may contain a mixtureof physiologically-acceptable cations.

A partial ester of a citrate anion will have one or two, but not allthree, of the carboxylate (i.e., —COO⁻) groups of citrate anion in anester form (i.e., —COO—R, where R is an organic group). In addition toone or two R groups, the partial ester of a citrate anion will includeone or two physiologically-acceptable cations (so that the total of theR group(s) and cation(s) equals three). The R group is an organic group,preferably a lower alkyl.

The citrate is preferably in association with protons and/or metalcations. Exemplary of such citrate compounds are, without limitation,citric acid, sodium dihydrogen citrate, disodium hydrogen citrate,trisodium citrate, trisodium citrate dihydrate, potassium dihydrogencitrate, dipotassium hydrogen citrate, calcium citrate, and magnesiumcitrate. In one embodiment, the citrate is present in the dialysateprecursor composition in the form of one or more of citric acid, sodiumdihydrogen citrate, disodium hydrogen citrate, potassium dihydrogencitrate, or dipotassium hydrogen citrate.

In a preferred embodiment, citric acid provides the source for thecitrate anions. In this embodiment, the citric acid functions as themain acidifying agent of the precursor composition. Citric acid is arelatively inexpensive physiological acid that, under ambientconditions, is in the form of a dry chemical powder, crystal, pellet ortablet. Any physiologically tolerable form of citric acid may be used tointroduce citrate anions to the composition. For instance, the citricacid may be in the form of a hydrate, including a monohydrate.

Citrate has been previously recognized to be able to function as ananti-coagulant in the bloodstream by binding calcium. Accordingly, thecitrate concentration of the dialysate precursor composition should beselected in view of its anti-coagulation properties. Unless othermeasures are taken, the citrate concentration should not exceed about900 mEq/L, and is preferably not more than about 200 mEq/L. When citrateconcentrations of 200-900 mEq/L are employed, the magnesium and/orcalcium concentration of the dialysate precursor composition must beincreased.

Although the citrate concentration should not be so great that itdetrimentally affects the coagulation properties of blood, theconcentration of citrate should be sufficiently high that it will beeffective to achieve and maintain the pH of the final dialysatecomposition at a physiologically-acceptable pH. Typically, a citrateconcentration that is one-quarter or less of the amount needed toachieve anti-coagulation can provide a dialysate composition with aphysiologically-acceptable pH. Thus, the present dialysate precursorcomposition should have a minimum citrate concentration of about 20mEq/L in order to provide the desired dialysate pH. In one embodiment,the dialysate precursor composition contains citrate at a concentrationranging from about 20 to about 900 mEq/L and in a preferred embodimentthe composition contains citrate at a concentration ranging from about70 to about 150 mEq/L. In a related embodiment, the invention provides adry dialysate precursor composition which, upon mixing with water,produced a dialysate precursor composition that contains citrate at aconcentration ranging from about 20 to about 900 mEq/L and in apreferred embodiment the composition contains citrate at a concentrationranging from about 70 to about 150 mEq/L.

Although citrate functions as an acidifying agent to lower the pH of adialysate composition, in one aspect the present invention introduces abuffering anion to the dialysate precursor composition in order tomaintain the pH of the final dialysate composition within aphysiologically-acceptable range. As used herein, “buffering anion”refers to a physiologically acceptable anion that adjusts and regulatesthe pH of a composition. Suitable buffering anions include, for example,acetate, lactate, and mixtures thereof (i.e., acetate and/or lactate),which are compounds that will minimize changes in hydrogen ionconcentration of a dialysate composition. As used herein, the phrase“lactate and/or acetate” means that either lactate alone, acetate alone,or a mixture of lactate and acetate may be used, or present, in thecomposition.

As used herein, “acetate” refers to an acetate anion, in any form,including acetic acid and salts of acetic acid. Acetate is an organic,monocarboxylate with the formula H₃C—COO⁻. The acetate salt is composedof one or more acetate anions in association with one or morephysiologically-acceptable cations. Exemplary physiologically-acceptablecations include, but are not limited to, protons, ammonium cations andmetal cations, where metal cations are preferred. Suitable metal cationsinclude, but are not limited to, sodium, potassium, magnesium andcalcium, where sodium and potassium are preferred, and sodium is morepreferred.

Exemplary acetate compounds of the present invention include, but arenot limited to, acetic acid, sodium acetate, sodium acetate trihydrate,potassium acetate, calcium acetate, calcium acetate monohydrate,magnesium acetate, and magnesium acetate tetrahydrate. In oneembodiment, the acetate of the dialysate precursor composition ispresent in the form of sodium acetate or potassium acetate, and in apreferred embodiment, acetate is in the form of sodium acetate.

As used herein, “lactate” refers to a lactate anion, in any form,including lactic acid and salts of lactic acid. Lactate is an organic,monocarboxylate with the formula H₃C—CH(OH)—COO⁻. A lactate salt iscomposed of one or more lactate anions in association with one or morephysiologically-acceptable cations. Exemplary physiologically-acceptablecations include, but are not limited to, protons, ammonium cations andmetal cations, where metal cations are preferred. Suitable metal cationsinclude, but are not limited to, sodium, potassium, magnesium andcalcium, where sodium and potassium are preferred, and sodium is morepreferred. When iron or trace element is desirably included in thecomposition, the metal cation may be iron cation (i.e., ferric orferrous cation) or may be a cation of a trace element, e.g., selenium orzinc cation.

Exemplary lactate compounds of the present invention include, but arenot limited to, lactic acid, sodium lactate, potassium lactate, calciumlactate and magnesium lactate trihydrate. In one embodiment, the lactateof the dialysate precursor composition is present in the form of sodiumlactate or potassium lactate, and most preferably lactate is in the formof sodium lactate. When iron or trace element is desirably included inthe composition, the lactate may be complexed with iron (i.e., ferric orferrous lactate) or may be complexed with a trace element, e.g.,selenium or zinc cation.

In general, the dialysate precursor composition will typically containmore equivalents of citrate than equivalents of buffering anion. Theprecursor composition preferably contains more equivalents of citratethan equivalents of acetate, lactate, or lactate+acetate. In oneembodiment, the dialysate precursor composition contains citrate at aconcentration ranging from about 20 to about 900 mEq/L together with abuffering anion selected from acetate and/or lactate at a concentrationranging from about 0.01 to about 150 mEq/L. In a preferred embodimentthe composition contains citrate from about 70 to about 150 mEq/L and abuffering anion selected from acetate and/or lactate at a concentrationranging from about 0.3 to about 125 mEq/L. In a related embodiment, thepresent invention provides dry compositions (e.g., pellets, tablets,powder) which upon mixing with water provide the dialysate precursorcompositions described above.

As the amount of citrate in the dialysate precursor composition isincreased, it tends to lower the pH of the dialysate made with theprecursor. With a lower dialysate pH, there is not as much need tobuffer the precursor to ensure that the dialysate pH does not rise to aphysiologically unacceptable level. Therefore, as a general rule, ashigher equivalents of citrate are used in the dialysate precursorcomposition, less equivalents of buffering anion are required.Conversely, as less equivalents of citrate are used in the dialysateprecursor composition, more equivalents of a buffering anion arerequired.

As used herein, the phrase “physiologically-acceptable cations” refersto cations normally found in the blood, plasma, or serum of a mammal, orcations that may be tolerated when introduced into a mammal. Suitablecations include protons, ammonium cations and metal cations. Suitablemetal cations include, but are not limited to, the cationic forms ofsodium, potassium, calcium, and magnesium, where sodium and potassiumare preferred, and sodium is more preferred. An ammonium cation, i.e., acompound of the formula R₄N⁺ where R is hydrogen or an organic group,may be used so long as it is physiologically acceptable. In a preferredembodiment, the cation is selected from hydrogen (i.e., proton), sodium,potassium, calcium, magnesium, and combinations thereof.

When the pH of a dialysate composition begins to increase (i.e., thedialysate becomes more basic) during the course of a dialysis treatment,the buffering anion, when present in an effective amount, prevents thepH of the dialysate composition from rising beyond aphysiologically-acceptable range. For compositions having the citrateconcentrations described above, and to provide the desired bufferingeffect, the precursor composition should contain from about 0.01 toabout 150 mEq/L of buffering anion, preferably selected from acetate,lactate and mixtures thereof. In a preferred embodiment, the precursorcomposition contains from about 0.3 to about 125 mEq/L of acetate and/orlactate. In one embodiment, the buffering anion is a mixture of acetateand lactate. In another embodiment, the buffering anion is acetate, andlactate is not present in the composition. In another embodiment, thebuffering anion is lactate, and acetate is not present in thecomposition.

With peritoneal dialysate, in order to facilitate the diffusion betweenblood and dialysate, it is desirable to maintain an osmotic gradientbetween the fluids by adding an osmotic agent to the dialysate. Thepresence of an osmotic agent in the peritoneal dialysate will encourageexcess fluid and metabolic waste byproducts to flow from the blood andinto the dialysate. A suitable osmotic agent for the precursor dialysatecomposition is sugar. The sugar is preferably selected from glucose(e.g., dextrose), poly(glucose) (i.e., a polymer made from repeatingglucose residues, e.g., icodextrin, made from repeating dextrose units),or fructose. While it is possible to make a dialysate precursor with nosugar, if sugar is to be added to the dialysate composition, it isgenerally dextrose. It is further appreciated that any biocompatible,non-sugar osmotic agent that functions as an equivalent could be aviable substitute. The sugar is typically present in the dialysateprecursor composition at a concentration of less than about 2,700 g/L.

A patient's blood serum contains several components including, forexample, proteins, carbohydrates, nucleic acids, and various ions.Typically, a dialysate composition prescribed by a physician is chosento reduce, increase, or normalize the concentration of a particularcomponent in the serum. Several cations may be prescriptively includedas part of the precursor dialysate composition. Suitable cations mayinclude, for example, sodium, potassium, calcium and magnesium. In thedialysate precursor composition, the preferred concentration range forsodium is from about 2,000 to about 5,000 mEq/L. The preferredconcentration range for potassium is less than about 250 mEq/L. Thepreferred concentration range for calcium is less than about 250 mEq/L.The preferred concentration range for magnesium is less than about 100mEq/L. As used herein, a concentration of less that about a recitedvalue includes zero. In a related embodiment, the present inventionprovides dry compositions (e.g., tablets, pellets, powder, etc.) whichupon mixing with water provide a dialysate precursor composition havingthe sodium, potassium, calcium, and magnesium concentrations recitedabove.

As used herein, “mEq/L” refers to the concentration of a particulardialysate component (solute) present in proportion to the amount ofwater present. More specifically, mEq/L refers to the number ofmilli-equivalents of solute per liter of water. Milli-equivalents perliter are calculated by multiplying the moles per liter of solute by thenumber of charged species (groups) per molecule of solute, which is thenmultiplied by a factor of 1,000. As an example, when 10 grams of citricacid are added to a liter of water, the citric acid is present at aconcentration of 10 g/L. Anhydrous citric acid has a molecular weight of192.12 g/mol; therefore, the number of moles per liter of citric acid,and consequently citrate anion (since there is one mole of citrate anionper mole of citric acid), is 10 g/L divided by 192.12 g/mol, which is0.05 mol/L. Citrate anion has three negatively charged species in theform of carboxylate groups. Accordingly, the citrate concentration of0.05 mol/L is multiplied by three and then by 1,000, in order to providea concentration of citrate in terms of mEq/L, which in the presentexample is 156 mEq/L of citrate anion.

A preferred water of the invention is treated in order that it isessentially pyrogen-free and sterile, and at least meets the purityrequirements established by the Association for the Advancement ofMedical Instrumentation (AAMI) for dialysate compositions. The water mayalso be referred to as treated water or AAMI-quality water. A monographdescribing water treatment for dialysate, monitoring of water treatmentsystems, and regulation of water treatment systems is available fromAAMI (Standards Collection, Volume 3, Dialysis, Section 3.2 WaterQuality for Dialysis, 3 ed., 1998, AAMI, 3330 Washington Boulevard,Arlington, Va. 22201) or through the Internet at http://www.aami.com. Inaddition, all of the other components of the precursor dialysatecomposition of the present invention are preferably at least UnitedStates Pharmacopeia (USP)-grade purity, which is generally a purity ofabout 95%. The purity of the components is preferably at least about95%, more preferably at least about 98%, and more preferably at leastabout 99%.

The dialysate precursor composition of the present invention willtypically have a pH ranging from about 1 to about 6.5, more typicallyfrom about 1 to about 4, more typically from about 2 to about 4, at atemperature of about 15° C. to about 40° C., before dilution withtreated water and base to afford the dialysate composition.

In a preferred embodiment, the dialysate precursor composition containscomponents including chloride at a concentration ranging from about2,000 to about 5,000 mEq/L; citrate at a concentration ranging fromabout 70 to about 150 mEq/L; acetate and/or lactate at a totalconcentration ranging from about 0.3 to about 125 mEq/L; at least onephysiologically-acceptable cation selected from hydrogen, sodium at aconcentration ranging from about 2,000 to about 5,000 mEq/L, potassiumat a concentration of less than about 250 mEq/L, calcium at aconcentration of less than about 250 mEq/L, and magnesium at aconcentration of less than about 100 mEq/L; and glucose (preferablydextrose) at a concentration of less than about 2,700 g/L, where thecomposition meets or exceeds the AAMI standard set for dialysate. In oneembodiment, the above-listed ingredients are the only active ingredientsin the composition. In a related embodiment, the present inventionprovides a dry composition which, upon mixing with water, provides thedialysate precursor composition having the components and componentconcentrations indicated above.

The present invention provides a method of forming the precursordialysate composition as described above. In this method, ingredientsare mixed together so as to provide the dialysate precursor composition.Thus, a source of chloride, a source of citrate, and a source(s) ofbuffering anion (e.g., acetate and/or lactate) are mixed together withtreated water, in amounts which ultimately provide the desiredconcentration of each, as set forth above. The non-aqueous components ofthe precursor dialysate composition may be pre-mixed and in the form ofa powder, pellet, tablet or other dry form, which is then readily mixedwith water so as to form the precursor dialysate composition. Suitablesources for these ingredients are well known in the art. Indeed, thechemical characteristics for the compounds used in the presentinvention, such as molecular weight and solubility, are available in theart such that one of ordinary skill in the art will know how to preparethe composition of the present invention. See, e.g., the Sigma andAldrich catalogs from Sigma-Aldrich (Milwaukee, Wis.;http://www.sial.com).

For example, the chloride source may be any of hydrochloric acid, sodiumchloride, potassium chloride, magnesium chloride, ammonium chloride, orthe like. The citrate source may be any of citric acid, sodiumdihydrogen citrate, disodium hydrogen citrate, trisodium citrate,trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassiumhydrogen citrate, calcium citrate, magnesium citrate, or the like. Theacetate source may be any of acetic acid, sodium acetate, sodium acetatetrihydrate, potassium acetate, calcium acetate, calcium acetatemonohydrate, magnesium acetate, magnesium acetate tetrahydrate, and thelike. The lactate source may be any of lactic acid, sodium lactate,potassium lactate, calcium lactate, magnesium lactate trihydrate, andthe like. Any or all of these chemicals are commercially available, inUSP-grade if desired, from many chemical supply houses including, forexample, Aldrich Chemical Co., Milwaukee Wis. The treated water may beobtained by following standard purification techniques, including, forexample, distillation and reverse osmosis. Alternatively, the treatedwater may be purchased commercially. Such treated water is used in all,or nearly all, dialysis clinics and accordingly is well known to one ofordinary skill in the art.

In one embodiment, the invention provides a method of forming adialysate precursor composition which includes the step of mixing water,chloride, citrate, at least one buffering anion selected from acetateand/or lactate, and at least one physiologically-acceptable cation, toprovide a composition having chloride at a concentration ranging fromabout 1,000 to 7,000 mEq/L, citrate at a concentration ranging fromabout 20 to 900 mEq/L, and at least one buffering anion selected fromacetate and/or lactate at a total concentration ranging from about 0.01to 150 mEq/L. The non-aqueous components of the dialysate precursorcomposition may be pre-mixed and in the form of a dry powder, pellet,tablet, etc., so that the method entails mixing water with this drypre-mixed composition.

In a preferred embodiment, sources of water, chloride, citrate, acetateand physiologically-acceptable cations are mixed so as to provide acomposition having water, chloride at a concentration ranging from about2,000 to about 5,000 mEq/L; citrate at a concentration ranging fromabout 70 to about 150 mEq/L; acetate at a concentration ranging fromabout 0.3 to about 125 mEq/L; at least one physiologically-acceptablecation selected from hydrogen, sodium at a concentration ranging fromabout 2,000 to about 5,000 mEq/L, potassium at a concentration of lessthan about 250 mEq/L, calcium at a concentration of less than about 250mEq/L, magnesium at a concentration of less than about 100 mEq/L; andglucose at a concentration of less than about 2,700 g/L, where thecomposition meets or exceeds the AAMI-quality standard set fordialysate.

In another aspect, the present invention provides a dialysatecomposition. The dialysate composition may, for example, be preparedfrom the dialysate precursor composition described above by addingtreated water and a base, preferably bicarbonate, to the precursorcomposition. Upon the addition of base and water, the dialysateprecursor composition provides a composition suitable for performingdialysis. As an alternative, a dry composition as also describedpreviously may be combined with water and base in order to prepare thedialysate composition.

For example, bicarbonate concentrate, or diluted bicarbonateconcentrate, may be added to the dialysate precursor composition, ordiluted dialysate precursor composition, to provide a dialysatecomposition according to the present invention. Typically, one volumepart of dialysate precursor composition is diluted with between 33 and45 parts of diluted base concentrate, to provide the dialysatecomposition. The dialysate precursor will contain citrate (as theprimary acidic ingredient of the acid concentrate), bicarbonate (as theprimary basic ingredient of the base concentrate) and buffering anionpreferably selected from acetate and/or lactate.

In one embodiment, the dialysate composition contains ingredientsincluding treated water; chloride at a concentration ranging from about20 to about 200 mEq/L; citrate at a concentration ranging from about 0.5to about 30 mEq/L; at least one buffering anion selected from acetateand/or lactate at a concentration ranging from about 0.01 to about 4.5mEq/L; bicarbonate; and at least one physiologically-acceptable cation.

In one embodiment, the dialysate composition includes one or more sugarsselected from glucose (preferably dextrose), poly(glucose) (preferably,poly(dextrose), e.g., icodextrin), and fructose at a concentration ofless than about 45 g/L. Instead, or in addition to sugar, the dialysatecomposition may contain one or more amino acids. Preferably, thedialysate composition contains water that meets or exceeds the purityrequirements established by AAMI for dialysate and all other componentshave at least USP-grade purity. In another preferred embodiment, thedialysate composition has a pH of about 5 to about 8.5 at a temperatureof about 25° C. to about 40° C., and more typically has a pH of about6.4 and 7.6 at this temperature range, and preferably has a pH of about7.2 to about 7.4.

In other embodiments, the dialysate composition contains ingredientsincluding water, chloride at a concentration ranging from about 40 toabout 150 (more preferably, from about 60 to about 120) mEq/L; citrateat a concentration ranging from about 1.5 to about 4.5 (more preferably,from about 2 to about 3) mEq/L; acetate and/or lactate at a totalconcentration ranging from about 0.01 to about 4.0 (more preferably,from about 0.2 to 0.5) mEq/L; bicarbonate at a concentration rangingfrom about 25 to about 45 mEq/L; at least one physiologically-acceptablecation selected from hydrogen, sodium at a concentration ranging fromabout 60 to about 190 (more preferably, from about 70 to about 150)mEq/L, potassium at a concentration of less than about 5 mEq/L, calciumat a concentration of less than about 5 mEq/L, and magnesium at aconcentration of less than about 2 mEq/L; and glucose (preferably,dextrose) at a concentration of less than about 45 (preferably, lessthan about 8) g/L, where the combined composition meets or exceeds theAAMI-quality standard set for dialysate.

In the dialysate compositions of the present invention, including theprecursors thereto, for either hemodialysis or peritoneal dialysis, inone embodiment of the invention the composition includes iron. Patientsundergoing dialysis are oftentimes iron deficient, where iron deficiencyis associated with anemia and other undesirable medical conditions.Currently, iron deficiency is most commonly addressed by either oraliron supplementation programs or by parenteral administration of iron.However, oral iron supplementation programs sometimes cause adversegastrointestinal effects, and there is also the difficulty that patientsdo not rigorously follow the program. Parenteral administration of ironovercomes certain difficulties associated with oral iron administrationand is the standard method if the patient is on peritoneal dialysis. Forhemodialysis patients it is injected into the venous blood line of thedialysis apparatus during treatment, which adds inconvenience and cost.One aspect of the present invention addresses these problems byproviding iron-containing dialysis compositions. As used in thiscontext, the term “iron” refers to both the ferric and ferrous forms ofiron, as well as complexes of iron.

The iron may be introduced into the composition in any convenient formthat is also compatible with the well-being of the patient (see, e.g.,“NKF-DOQI clinical practice guidelines for the treatment of anemia ofchronic renal failure” Am J. Kidney Dis. 30:S192-S237, 1997). Forexample, iron dextran (ferric hydroxide dextran complex, CAS RegistryNo. 9004-66-4) is currently administered to hemodialysis patients viaparenteral administration. (see, e.g., “Iron dextran treatment inperitoneal dialysis patients on erythropoietin” Perit. Dial. Bull.8:464-466, 1992; and Goldberg, L., “Pharmacology of parenteral ironpreparations” Iron in Clinical Medicine 78:74-92, 1958). In lieu of, orin addition to, dextran, the iron may be complexed with othersacchamides or polysaccharides, e.g., iron saccharate or gluconatecomplex. Any of these iron saccharide complexes may be included in adialysate composition of the present invention. As another example, theiron may be introduced via ferric pyrophosphate (see, e.g., Gupta, A.,et al. “Dialysate iron therapy: Infusion of soluble ferric pyrophosphatevia the dialysate during hemodialysis” Kidney International55:1891-1898, 1999). In order to create a water-soluble form of ferricpyrophosphate, the ferric pyrophosphate may be prepared by chemicalreaction with citric acid and sodium hydroxide. As a final example, theiron may be introduced to the dialysate composition via either or bothof ferric citrate (CAS Registry No. 3522-50-7) or ferrous citrate. Inone aspect of the invention, the iron is introduced to the dialysate viaan iron salt of citrate.

Regardless of the form in which the iron is added to the dialysate, theamount of iron being added should be a therapeutically effective amount.This amount will vary somewhat depending on the specific condition ofthe patient and the goals of the attending physician. However,generally, an iron concentration in dialysate ranging from 0.1 to 300micrograms/deciliter will be a suitable concentration. Because thisamount will typically vary from patient to patient, a commercialcitrate-containing product may be prepared that does not contain anyiron, and the product may be “spiked” with the desired amount of iron inthe hospital or other site where the patient is undergoing the dialysistreatment.

In the dialysate compositions of the present invention, including theprecursors thereto, for either hemodialysis or peritoneal dialysis, inone embodiment of the invention the composition includes one or moretrace elements. Studies have shown that dialysis, and particularlymaintenance dialysis, causes loss of trace elements from the patientundergoing the dialysis. The present invention provides compositions andmethods to offset that loss of trace elements by incorporating traceelements into a composition of the present invention.

Any one or more trace elements may be included in a composition of thepresent invention (see, e.g., Zima, T., et al., Blood Purif.17(4):187-198, 1999 and Zima, T. et al. “Trace Blood Purif.16(5):253-260, 1998). For example, selenium may be included in acomposition of the present invention (see, e.g., Krizek, M. et al.“Influence of hemodialysis on selenium blood levels” Sb Lek101(3):241-248, 2000; and Napolitano G., “Thyroid function and plasmaselenium in chronic uremic patients on hemodialysis treatment” Biol.Trace Elem. Res. 55(3):221-30, December 1996). Another trace elementthat may be included in a composition of the present invention is zinc.Chromium, manganese and molybdenum are yet three other trace elementsthat may be included in the dialysate composition.

The trace element may be added to the composition via any salt orcomplex of the element. For example, regardless of the identity of thetrace element, in one aspect of the invention the element may be addedto a composition of the present invention via its citrate salt. However,other suitable forms may be used, e.g., zinc sulfate for zinc, seleniumsulfide for selenium. The amount of trace metal to be included in acomposition of the present invention should be selected in view of thespecific condition of the patient and the goal of the attendingphysician. However, generally, the Recommended Daily (or Dietary)Allowance (RDA) of trace elements, as set forth by the Food andNutrition Board of the National Academy of Sciences/National ResearchCouncil, is a good guideline to follow (see, e.g., Recommended DietaryAllowances: National Academy of Sciences; 10th ed., 1989; see alsoDietary Reference Intakes (DRIs): National Academy of Sciences, 1997).Because this amount may vary from patient to patient, a commercialcitrate-containing product may be prepared that does not contain anytrace elements, and the product may be “spiked” with the desired traceelements, in the desired amounts, in the hospital or other site wherethe patient is undergoing the dialysis treatment.

In another aspect, the present invention provides a method of forming adialysate composition. In a preferred embodiment, the method includescombining the dialysate precursor composition, as described above, witha base concentrate, preferably a bicarbonate base concentrate, andtreated water as needed to provide prescribed concentrations of solutesin the dialysate. The base concentrate contains water, bicarbonate, andhas a pH of greater than 7. The pH will be greater than 7 because of thepresence, in the concentrate, of one or more “bases.” Base concentrateis currently used in most dialysis clinics. The base in a typical baseconcentrate is bicarbonate, also known as hydrogen carbonate, having thechemical formula HCO₃. Bicarbonate carries a net negative charge, andaccordingly will be associated with a positively charged species.Suitable positively charged species include physiologically-acceptablemetal cations such as the cationic forms of sodium, potassium, calciumand magnesium.

The base from which the base concentrate is almost universally preparedin dialysis clinics is sodium bicarbonate, and this is the preferredbase in the present compositions and methods. The bicarbonateconcentrate in a dialysate is preferably from about 25 to 40 mEq/L.Acetate base is not a preferred base.

Optionally, the sodium bicarbonate in a base concentrate may bereplaced, in part, with a different physiologically-acceptable base. Theanionic portion of a suitable replacement for sodium bicarbonate may be,for example, carbonate, lactate, citrate and acetate. Accordingly, thebase for a base concentrate may be selected from the salt forms of anyof bicarbonate and, optionally, carbonate, lactate, citrate and acetate.Also present in the salt forms will be one or morephysiologically-acceptable cations selected from sodium, potassium,calcium and magnesium. These salts and acids are electronically neutral,i.e., there are an equal number of negative and positive charges.

Preferably, the dialysate precursor composition and the base concentrateare mixed so as to arrive at a dialysate composition that containsingredients including water, chloride at a concentration ranging fromabout 40 to about 150 (more preferably, from about 60 to about 120)mEq/L; citrate at a concentration ranging from about 1.5 to 15.0,preferably from about 1.5 to about 4.5 (more preferably, from about 2 toabout 3) mEq/L; acetate and/or lactate at a total concentration rangingfrom about 0.01 to about 4.0 (more preferably, from about 0.2 to 0.5)mEq/L; bicarbonate at a concentration ranging from about 25 to about 45mEq/L; at least one physiologically-acceptable cation selected fromhydrogen, sodium at a concentration ranging from about 60 to about 190(more preferably, from about 70 to about 150) mEq/L, potassium at aconcentration of less than about 5 mEq/L, calcium at a concentration ofless than about 5 mEq/L, and magnesium at a concentration of less thanabout 2 mEq/L; and glucose (preferably, dextrose) at a concentration ofless than about 45 (preferably, less than about 8) g/L, where thecombined composition meets or exceeds the AAMI-quality standard set fordialysate. Higher concentrations of citrate could typically be used whena patient is simultaneously infused with excess calcium.

In dialysate compositions of the invention, the citrate-containingdialysate precursor composition is combined with the base concentrate soas to arrive at a final dialysate composition having a pH in thephysiological range of 5 to 8.5, and preferably from about 7.2 to about7.4.

In another aspect, the present invention provides an aqueousacid-concentrate composition useful in hemodialysis that contains, at aminimum, water, chloride, citrate, and cations to provide for a neutral(i.e., no net charge) composition, but does not contain any ofbicarbonate, acetate or lactate. The water is “treated water” as definedherein, or a water of even greater purity, and each of the chloride andcitrate is USP-grade quality or better (for example, reagent grade,preferably of at least 99% purity). In a related aspect, the aqueousacid-concentrate composition is prepared from water and a solidcomposition that, upon mixing with water, affords the aqueousacid-concentrate composition having the components described above.Thus, the present invention also provides, in one aspect, this solidcomposition.

The aqueous acid-concentrate composition contains chloride at aconcentration of about 1,000 to about 7,000, preferably of from about2,000 to about 5,000 mEq/L; citrate at a concentration ranging fromabout 20 to about 200, preferably from about 70 to about 150 mEq/L; andsufficient physiologically-acceptable cations to provide for a neutral(i.e., no net charge) composition, where the composition has a pH ofless than 4, preferably between about 2 and about 3, and more preferablyabout 2.2 to 2.8, and does not contain any of bicarbonate, acetate, orlactate. The present invention also provides the same composition in awater-free form which, upon mixing with water, will form the aqueousacid-concentrate composition described above. The water-free form may bein the form of, e.g., a pellet, tablet or powder.

Although this aqueous acid-concentrate composition does not contain anyof bicarbonate, acetate or lactate, it is still usefully employed indialysate manufacture. For instance, it provides a convenient stocksolution to which may be added bases and/or salts. Since it is a liquid,it is conveniently employed as the acid concentrate in traditionaldialyzers that employ the three-stream proportionate pumping mechanismfor making dialysate. Care should, however, be taken when combiningbase, such as bicarbonate, with the aqueous acid-concentratecomposition, in order that the desired pH of the final dialysate isobtained.

In a related embodiment, the invention provides a method of preparingdialysate, wherein a basic solution containing water and at least one ofbicarbonate, carbonate, acetate, lactate, and citrate having a pH ofgreater than 7 is mixed with the aqueous acid-concentrate compositiondescribed above, i.e., an acidic solution having a pH of less than 4containing, at a minimum, chloride, citrate, and cations, the cationsproviding for an electronically neutral composition, where this acidicsolution does not contain any of bicarbonate, acetate or lactate.According to this method, the relative amounts of basic and acidicsolutions that are combined should be carefully tailored so as toachieve a desired dialysate pH, at all times throughout a dialysistreatment session. Typically, that desired dialysate pH is within therange of 6.8 to 7.8.

While citric acid-containing hemodialysate compositions are known in theart, see U.S. Pat. No. 5,252,213 of Ahmad et al., such compositions aredisclosed as dry pellets (or other like solid form) which are dissolvedin water to provide the hemodialysate composition. Those compositionsprovide a convenient source of all of the components of a hemodialysatecomposition, and are intended to be combined with water and essentiallyno other ingredients, before being used in a hemodialysis treatment.Thus, each pellet contains both the acidic and basic components of ahemodialysate composition which ensures the pH of the resultinghemodialysate.

The present invention makes an aqueous acid concentrate that may be usedin the preparation of either hemodialysate or peritoneal dialysate. Thecitric acid concentrate is intended to be combined with treated waterand base concentrate, as is currently the practice in dialysis clinics,so as to afford the dialysate composition. In clinics, the pH of thebase concentrate, which typically contains sodium bicarbonate, can varywidely and affect the resulting dialysate pH. Therefore, when using acitric acid-containing acid concentrate in the manner according to thepresent invention, the concentrate should contain a buffering agent inorder to maintain the resulting dialysate pH within a pre-determined,physiologically-acceptable range throughout the duration of the dialysistreatment. Buffering is required because increasing the amount of citricacid to lower the dialysate pH may cause a significant decrease in serumcalcium concentration. This need for a buffer with citric acidconcentrate is a departure from the practice in the art.

Most dialysates in use today use acetic acid as the acidifying agent tokeep the pH of the final dialysate within an acceptable physiologicalrange. As noted above, the ‘acid concentrate’ that is used in mosthemodialysis treatments today is shipped as a liquid. The concentrate isin liquid form because acetic acid is a liquid acid. Although thissolution is far more concentrated than the final dialysate which isactually used to purify a patient's blood (it can be as much as 45 timesmore concentrated), still three-quarters of its weight and volume iswater. The present invention utilizes citric acid, rather than aceticacid, as the main acidic material in an acid concentrate.

In an acid concentrate that contains citrate, the citrate will beprimarily in the form of citric acid. There are certain ramifications ofusing citric acid in an acid concentrate for dialysate. For example,citric acid forms citrate in the blood which binds with free magnesiumand calcium. In fact, the strong binding of calcium with citrate is usedby blood banks to prevent clotting in donated blood. While the level ofcitric acid used in the dialysate of the present invention is only afraction (less than one-quarter) of the amount needed to achievemeasurable anticoagulation, medical prudence dictates using the leastamount of citric acid possible in a dialysate in order to minimizeundesired calcium binding in the blood. When dialysate is prepared from45× dilution of precursor dialysate, and the precursor dialysate hascitrate concentrations within the range of 200-900 mEq/L, then theprecursor preferably has elevated levels of calcium and/or magnesium tocompensate for the extent to which citrate will bind serum calcium andmagnesium.

The amount of citrate present in the acid concentrate of the inventionshould be the least amount necessary to achieve a final dialysate pHwithin the range of 7.2 to 7.4. We have found that using about 7 gramscitric acid per liter of water in an acid concentrate (providing aconcentration equal to 2.4 mEq/L) would minimize the calcium binding andachieve an acceptable dialysate pH.

However, the use of citrate in an acid concentrate led to anintermittent problem when the dialysate was used in a clinical setting.Generally, late in a dialysis session (usually in the last hour oftreatment) some dialysis machines would sound an alarm due to high pH.This problem was traced to the base solution.

Bicarbonate is the basic material present in most base solutions. Inmost dialysis clinics, the bicarbonate solution is made by the clinicstaff just before use. The procedure often can involve pouring apre-determined amount of sodium bicarbonate (typically one package) intoa jug, adding a measured amount of water and manually mixing (usually byshaking the container). Any, some, or all of the following factors maycause variations in the pH of the bicarbonate from the expectedstandard: the amount of water added can be more or less than specified,the mixing can be insufficient to thoroughly put all the sodiumbicarbonate powder into solution, the container could be left sittingfor a period before use, or the patient has a long dialysis treatment.

When carefully measuring and adequately mixing the bicarbonate, the pHof the concentrated solution was 7.85 (±0.05). However, in practice,samples of bicarbonate concentrate that are prepared by clinic staff hada range of pH values from 7.78 to 8.13. Furthermore, the pH of theresidual bicarbonate concentrates that had just been used for ahemodialysis treatment were found to range from 7.9 to 8.24. Wespeculate that this variation in pH, most noticeably observed in the‘spent’ dialysate, may be from any one of, or a combination of, thefollowing factors:

-   -   Insufficient water was added to the base concentrate, causing a        higher than desired concentration of bicarbonate.    -   Inadequate mixing of the powder and water, allowing some        settling of the powder and therefore a more concentrated        bicarbonate solution and rising pH late in the dialysis        treatment (at which time the powder has completely dissolved).    -   The bicarbonate concentrate releases carbon dioxide over time,        thereby causing slowly increasing pH.

One way to ensure against the pH rising to the alarm threshold during adialysis treatment is to increase the amount of acid used, which causesa more acidic dialysate. However, increasing the amount of citric acidalso increases the amount of calcium binding—accordingly, this approachmust be used with caution. An alternative approach taken according tothe present invention is to mitigate the effects of an increase indialysate pH which is caused by a rising pH of the bicarbonateconcentrate, through inclusion of a buffering agent in the acidconcentrate.

Acetate and/or lactate were selected as the preferred buffering agentsin the present invention. Each of these anions is found naturally in theblood of dialysis patients. Sodium acetate is a preferred buffer becauseit contains the same ingredients, sodium and acetate, that are invirtually all current dialysates (provided from the sodium chloride andacetic acid).

Surprisingly, there is not a linear relationship between the amount ofsodium acetate buffer present in the acid concentrate and the pH of thefinal dialysate solution. It might be expected that adding increasingamounts of this acidic buffer to an acid concentrate would cause alinear decrease in the pH of the final solution. However, this is notthe case. Within a narrow range the sodium acetate causes a significantdecrease in the pH of the dialysate. However, this buffering action ofthe sodium acetate is only observed when the pH of the bicarbonateconcentrate exceeds 8.0. At higher pH values of the bicarbonateconcentrate, the buffering action of the acetate is more apparent.

This effect is shown in the FIGURE. The chart of the FIGURE illustratesthe resulting dialysate pH obtaining using a relatively high bicarbonateconcentration at pH 8.14 combined with treated water and the presentinvention's dialysate precursor using 2.4 mEq·L of citrate andincreasing the sodium acetate concentration from 0 to 3.5 grams perliter. As shown in the FIGURE, increasing the concentration of sodiumacetate beyond a certain point does not increase the sodium acetate'sbuffering action nor does it make the buffering action apparent at lowervalues of bicarbonate pH. While not wishing to be bound by theory, thefollowing is suggested to explain the surprising effect of using acetatein the acid concentrates of the invention.

Citric acid is a multi-protic acid. It contains three labile hydrogenatoms that can contribute to the acidity of a solution. There is aseparate equilibrium associated with the liberation of each hydrogenion:

H₃A

 H⁺ + H₂A⁻ K_(al) = 7.10 × 10⁻⁴ at 20° C. (pKa = 3.14) H₂A⁻

 H⁺ + HA²⁻ K_(a2) = 1.68 × 10⁻⁵ at 20° C. (pKa = 4.77) HA²⁻

 H⁺ + A³⁻ K_(a3) = 6.4 × 10⁻⁶ at 20° C. (pKa = 6.39)where A represents the citrate anion. At a pH greater than 7 almost allof the citric acid is dissociated and the predominant species are H⁺ andA³⁻.

Acetic acid is a monoprotic acid, i.e., it contributes only one labilehydrogen atom to the solution and there is only one equilibrium constantfor the equilibrium:

HAc

 H⁺ + Ac⁻ K_(a) = 1.76 × 10⁻⁵ at 25° C. (pKa = 4.75)where Ac represents the acetate anion. When sodium acetate (NaAc) isintroduced to aqueous solution it dissolves completely into sodium ions(Na⁺) and acetate ions (Ac⁻). The sodium is considered to be a‘spectator’ ion—it does not participate in any equilibria. The acetate(Ac⁻) anion undergoes hydrolysis:

Ac⁻ + H₂O

 HAc + OH⁻ K_(b) = K_(w)/K_(a) = 10⁻¹⁴/1.76 × 10⁻⁵ = 5.6 × 10⁻¹⁰

A buffer is a solution whose composition is designed to resist changesin pH. Small amounts of acid or base can be added to a buffer and the pHwill change very little. These statements imply that the buffersolutions are able to react with both H⁺ (also commonly written as H₃O⁺)and OH⁻ ions. Two common kinds of buffer solutions are ones whichcontain (1) a weak acid plus a salt of the weak acid, and (2) a weakbase and a salt of the weak base. A less common type contains a weakacid (e.g., citric acid) and a salt of another weak acid (e.g., sodiumacetate which is derived from acetic acid).

For simple aqueous solutions, the buffering action can often becalculated based on available data, specifically: concentration of acid,concentration of salts, temperature, and appropriate equilibriumconstants, K_(i). The situation with the acid concentrates anddialysates of the present invention is more complex. Additionalequilibria are introduced by the addition of calcium (Ca) and magnesium(Mg) to the dialysate. These metal ions have their own equilibria withcarbonate, acetate, and citrate ions. Equilibrium constants K_(i), forsome of the equilibria are not available and so their impact on the pHof a dialysate formulation cannot be absolutely predicted. Directmeasurement of solution pH by titrimetric methods may be used in theformulation of the dialysate. The predominant equilibria in solution aregiven by (not an exhaustive list):

H₃A

 H⁺ + H₂A⁻ K_(al) = 7.10 × 10⁻⁴ at 20° C. (pK_(a) = 3.14) H₂A⁻

 H⁺ + HA²⁻ K_(a2) = 1.68 × 10⁻⁵ at 20° C. (pK_(a) = 4.77) HA²⁻

 H⁺ + A³⁻ K_(a3) = 6.4 × 10⁻⁶ at 20° C. (pK_(a) = 6.39)where A represents the citrate anion.

Ac⁻ + H₂O

 HAc + OH⁻ K_(b) = K_(W)/K_(a) = 10⁻¹⁴/1.76 × 10⁻⁵ = 5.6 × 10⁻¹⁰where Ac represents the acetate anion.

H₂O

 H⁺ + OH⁻ K_(w) = 10⁻¹⁴ at 25° C. (Also written as 2H₂O

 H₃O⁺ + OH⁻) HCO₃ ⁻

 H⁺ + CO₃ ⁻ Ca²⁺ + 2Ac⁻

 CaAc₂ K_(sp) = solubility product constant, i.e., the solubility ofcalcium acetate Mg²⁺ + 2Ac⁻

 MgAc₂ K_(sp) = solubility product constant, i.e., the solubility ofmagnesium acetate 3Ca²⁺ + 2A³⁻

 Ca₃A₂ K_(sp) = solubility product constant, i.e., the solubility ofcalcium citrate 3Mg²⁺ + 2A³⁻

 Mg₃A₂ K_(sp) = solubility product constant, i.e., the solubility ofmagnesium citrate

Since the A³⁻ species predominates at a pH above 7.0, the calcium andmagnesium equilibria with lower citrate ions (HA²⁻ and H₂A⁻) are notconsidered.

Ca²⁺ + CO₃ ²⁻

 CaCO₃ K_(sp) = solubility product constant, i.e., the solubility ofcalcium carbonate Mg²⁺ + CO₃ ²⁻

 MgCO₃ K_(sp) = solubility product constant, i.e., the solubility ofmagnesium carbonate

If all of the constants and concentrations were known for 37° C., thenthe above equations could be set into a matrix and the pH and bufferingaction could be obtained by calculation. The situation is furtherrestrained by the requirement to keep the pH within a physiologicalrange (especially near the end of dialysis when the pH of thebicarbonate concentrate tends to rise). Normally, this could beaccomplished with the addition of more (citric) acid, however, this isprecluded by the need to keep the concentration of citrate ions (fromcitric acid) as low as possible. As discussed below, this is requiredbecause of the tendency of calcium and magnesium to combine with citrateions thus lowering the serum levels of calcium and magnesium toclinically unacceptable levels. The solution to this problem is found inApplicants' selection of the buffer.

Sodium citrate is not used in the buffer because of the aforementionedneed to maintain an acceptably low total citrate ion concentration.Acetate or lactate may be used because of (1) their appropriatebuffering action, (2) cost, (3) acetate ions (which are preferred) arealready used (from acetic acid) in dialysate formulations and thus nonew variable is introduced to the chemistry of the dialysate.

The buffering action manifests itself by lowering the pH of thedialysate to physiological, non-alarm levels when the pH of thebicarbonate is high—either from incorrect mixing or the passage of timesince mixing. When the bicarbonate pH is appropriate, the buffer ispresent, but it is transparent to the operation of the dialysate. Whenbicarbonate concentrate solutions were used with a pH of <8.0 thebuffering action was not apparent. When bicarbonate concentratesolutions of 8.1<pH<8.3 were used, the buffering action was evident (seeFIGURE). The buffering action is particularly evident for sodium acetateconcentrations between 0.5 and 3.0 g per liter of acid concentrate,where this is a preferred range for the acid concentrates of the presentinvention.

In another aspect, the present invention provides citrate-containingcompositions particularly suitable for peritoneal dialysis (PD). Thesecomposition may be in either solid or liquid form, i.e., either amixture of dry ingredients, which is a precursor to the peritonealdialysate, or a solution of various solutes, which itself is aperitoneal dialysate. The mixture of dry ingredients contains, at aminimum, chloride, citrate, bicarbonate and dextrose, along with one ormore cationic species that provide a neutral (i.e., no net charge)composition. The solution form of the PD composition contains, at aminimum, water in addition to the above-listed minimum ingredientsrequired for the dry composition. Whether in solid or liquid form, thecitrate acid-containing compositions suitable for peritoneal dialysisare sterile.

The peritoneal dialysate of the present invention (i.e., the PD solutiondialysate) contains water in addition to the following ingredients, inthe indicated amounts, where the amounts are expressed in terms of mEqper liter of the PD solution: citrate (0.5-6, preferably 1.5-4.5, morepreferably 2-3); chloride (20-200, preferably 40-150, more preferably60-120); and bicarbonate (5-100, preferably 10-70, more preferably30-40). In addition, the solution form of the PD composition containsglucose at a concentration, in terms of g per liter of the solutionform, of 10-100, preferably 20-80, more preferably 40-60. In addition,the solution form of the PD composition contains a sufficient number ofphysiologically-acceptable cations to neutralize all of the citrate,chloride, bicarbonate, and any other anionic species that may be presentin the composition. This PD solution dialysate is sterile, as requiredfor all dialysates approved for peritoneal dialysis by the U.S. Food &Drug Administration.

In a preferred embodiment, the solution form of the PD compositioncontains acetate and/or lactate, where in total these two anions arepresent in an amount, expressed in terms of mEq per liter of PDsolution, of 0.01-10, preferably 0.1-1, more preferably 0.25-0.75. Thecationic species present in the PD solution are essentially within thesame concentration ranges as previously set forth herein for cationicspecies (i.e., sodium, magnesium, calcium and potassium) in thehemodialysis compositions.

The present invention provides a dry composition which, upon combinationwith sterile water, will generate the above-described PD solutiondialysate. This dry composition is, itself, sterile. According to oneapproach, such a dry composition can be described in terms of grams of aspecific ingredients per each (one) gram of citrate. Using these terms,the dry composition contains chloride in an amount of 5-50, preferably10-40, more preferably 20-30; bicarbonate in an amount of 1-50;preferably 5-30, more preferably 10-20; and glucose in an amount of100-600; preferably 150-500, more preferably 200-350, where each ofthese values are grams per 1 gram of citrate. In calculating theseamounts, the formula weights for citrate, chloride, and bicarbonate are189.1 g/mol, 35.5 g/mol and 61.0 g/mol, respectively, where each ofchloride and bicarbonate carry a single charge, while citrate carries atriple charge. The dry PD composition contains sufficient cationicspecies to provide a neutral (no net charge) composition. In addition,the pH of the resulting solution will be within a physiologicallytolerable range, preferably within the range 6.4-7.6.

According to another approach, the content of the dry PD composition canbe described in terms of the number of milli-equivalents of a specificcharged species present in the composition per each (one)milli-equivalent of citrate present in the composition. In these terms,the dry composition contains chloride in an amount ranging from 1-200,preferably 10-100, more preferably 30-50 mEq; and bicarbonate in anamount ranging from 1-50, preferably 5-30; more preferably 10-20 mEq. Inaddition, the dry PD composition contains glucose in an amount of100-600; preferably 150-400, more preferably 200-300, where each ofthese values are grams per 1 gram of citrate.

Both the peritoneal dialysate and the dry precursor thereto arenecessarily sterile in order to be useful in peritoneal dialysis.Accordingly, the preparation of each is necessarily conducted understerile conditions, and/or the resulting composition is rendered sterileby appropriate sterilizing treatment. According to one embodiment, thedry PD composition is prepared by combining sodium chloride (5.67 g),calcium chloride dihydrate (0.26 g), magnesium chloride hexahydrate(0.10 g) sodium bicarbonate (2.94 g), anhydrous citric acid (0.15 g),sodium acetate trihydrate (0.041 g) and dextrose (42.5 g), where each ofthe listed chemicals is in sterile form, and the combining procedure isconducted in a sterile environment. This dry composition contains 0.15 gcitrate, 3.6 g chloride, 2.1 g bicarbonate and 42.5 g glucose which, interms of each gram of citrate, is 24 g chloride, 14 g bicarbonate and283 g dextrose, and in terms of each milli-equivalent of citrate is 42mEq chloride and 14.5 mEq bicarbonate.

The dry PD composition, and the peritoneal dialysate prepared therefrom,is described in terms of anionic species because each anionic speciesmay be introduced into the composition in any dry form that isphysiologically acceptable and contains the anionic species of interest.Thus, for example, “citrate” can be introduced into the dry compositionin any dry form that contains citrate. Examples are citric acid(anhydrous), citric acid monohydrate, trisodium citrate, citric aciddisodium salt sesquihydrate, citric acid monosodium salt, citric acidtripotassium salt monohydrate, etc. Likewise, each of the bicarbonateand chloride may be introduced simultaneous with cations selected fromsodium, potassium, magnesium and calcium, and may be in anhydrous orhydrate forms. Accordingly, the dry composition is described in terms of“chloride”, “citrate”, and “bicarbonate”, rather than specifying anyparticular salt or protonated form thereof.

The chloride is present in the dry composition in the form of a salt.Suitable chloride salts include, without limitation, sodium chloride,potassium chloride, calcium chloride, and magnesium chloride. Apreferred chloride salt is sodium chloride.

The citrate is present in the dry composition in form of an acid and/ora salt. Citric acid is a suitable acid form of citrate. Trisodiumcitrate, tripotassium citrate, and calcium citrate (i.e., tricalciumdicitrate) are all suitable salt forms of citrate. The citrate may be ina mixed acid/salt form, i.e., complexed simultaneously to one or moreprotons and one or more metal cations. Typical examples of citrate inmixed acid/salt form include, without limitation, potassium dihydrogencitrate, dipotassium hydrogen citrate, and disodium hydrogen citrate. Apreferred citrate is citric acid.

The bicarbonate is present in the dry composition in the form of a salt.Suitable bicarbonate salts include, without limitation, sodiumbicarbonate, and potassium bicarbonate. A preferred bicarbonate salt issodium bicarbonate.

Glucose is a component of most of the currently used peritonealdialysates, and is incorporated into the peritoneal dialysate (andprecursor thereto) of the present invention in order to provide thebenefits that glucose is known to provide to peritoneal dialysates. Forexample, glucose is primarily useful as an osmotic agent, as discussedpreviously, and is also recognized to mitigate some of the undesirableside-effects of peritoneal dialysis. The glucose may also provide somenutritional supplement to the subject undergoing to the dialysistreatment. The most typical glucose isomer currently used in peritonealdialysate is dextrose, i.e., α-D-glucose. This is a commonly knownmaterial of commerce, and is available in both hydrated and anhydrousforms. Either form may be used in the present PD composition.

Although the dry composition will be dry to the touch, it may containsome water. For instance, several of the salts and acids mentioned aboveas suitable ingredients for the dry PD composition are commonlyavailable in hydrated form. Such hydrated forms are suitably used inpreparing the dry PD composition provided herein. Each of theabove-mentioned ingredients of the dry PD composition is available frommany commercial supply houses. See, e.g., Sigma-Aldrich(http://www.sial.com). Preferably, the ingredients are of United StatesPharmacopeia (USP)-grade purity or higher, which is generally recognizedas a purity of at least about 95%.

Optional ingredients may be present in the dry PD composition. Suitableoptional ingredients include, without limitation, amino acids.

The dry PD composition is readily prepared simply by mixing togetherweighed quantities of the various dry sterile ingredients under sterileconditions. Mixing is readily accomplished by agitating a combination ofthe ingredients until a homogeneous mixture results. The pre-weighed drymixture may be packaged in hermetically-sealed packages for conveniencein shipping, and to allow a technician to more easily prepare a solutionform of the dry composition.

The dry dialysate powder technology of the present invention allows thepreparation of peritoneal dialysate. This aspect of the inventioncreates a unique peritoneal dialysate using, in a preferred embodiment,citric acid as the acidifier, dextrose at concentrations exceeding 2.0%and bicarbonate as the basic anion. Other ingredients would includewater as well as chloride, sodium, potassium, magnesium, and calcium,which could all be included at the concentration ranges specified forhemodialysis dialysate. Peritoneal dialysate would require no precursor(other than the dry powder) since the volumes of dialysate used pertreatment are just a small fraction of the amounts used in hemodialysis.Making the peritoneal dialysate just prior to use (i.e., by addingsterile water to the sterile dry PD powder) would allow the use ofbicarbonate as the basic anion. Normally, bicarbonate cannot be used inPD because solutions of it with citric acid do not have sufficientlong-term stability to permit storage. To overcome this stabilityproblem, currently used PD compositions typically contain lactate(rather than bicarbonate) as the basic anion. However, some health careprofessions prefer bicarbonate as the basic anion, and the presentinvention addresses that need.

The precise order in which the sterile water and dry ingredients arecombined is unimportant. As one option, sterile water may be added tothe dry PD composition described above. As another option, a desiredvolume of sterile water may be provided, and to this may be added eachof the various other (sterile) ingredients of the solution PDcomposition. Typically, the final solution should be stirred orotherwise agitated, e.g., shaken, to form a homogeneous composition.“Handbook of Dialysis” 2^(nd) Ed. Daugirdas, J. T. and 1 ng T. S., eds.(Little, Brown, Boston, 1994) provides an extensive discussion ofperitoneal dialysis (as well as hemodialysis).

Physiological Effects

Citric acid was identified as a potential acidifying agent for dialysatebecause it is an inexpensive physiological acid. In addition, it has anextensive history of use in blood banks and also has been successfullyused for regional anticoagulation in hemodialysis. Both these prior usesare based on the calcium binding effect of the citric acid. It isempirically observed that blood will coagulate if the concentration offree calcium in the blood is above a certain critical concentration. Ascitric acid is added to blood, the citrate binds with the free calciumand reduces its concentration. When the free calcium concentration isreduced to a certain point, the blood will no longer coagulate.

In the present invention, citric acid is employed in dialysate as anacidifying agent to reduce the pH of the dialysate. However, using morethan about 2.4 mEq/L of citric acid in dialysate may possibly cause adecrease in serum calcium concentration, which may be clinicallyundesirable. At the level of 2.4 mEq/L of citric acid in dialysate, theincrease in blood citrate concentration is typically small enough to notcause any noticeable detrimental effect on the coagulation behavior ofblood. Indeed, there is typically no measurable increase in a patient'sclotting time beyond that already achieved with their normalanticoagulation medicine, heparin.

Generally, kidney failure patients suffer from chronic acidosis. Theirkidneys cannot rid the body of the H⁺ ions produced during normalmetabolism. As a consequence, their bodies use excessive amounts ofbicarbonate to buffer excess H⁺ ions. Because of the constant use ofbicarbonate to neutralize acid, these patients have lower than normallevels of bicarbonate (carbon dioxide) when they arrive for theirdialysis treatment. Traditionally, dialysis treatment seeks to correctan acidosis problem by using dialysate that contains higher than normalserum concentrations of bicarbonate. Thus, during treatment, the bloodbicarbonate increases because of diffusion of some of this excessbicarbonate into the blood which helps restore total body bicarbonate.However, the traditional dialysis with a dialysate bicarbonateconcentration of about 37 mEq/L is often not enough to maintain normalblood bicarbonate between dialysis sessions. Consequently, by the timethe patient comes for the next dialysis session, the blood bicarbonateis again subnormal. The buffered citrate dialysate(s) of the presentinvention have shown some effect at replenishing the body's bicarbonatelevels, thus helping to treat chronic acidosis.

The following examples are provided for purposes of illustration, notlimitation.

EXAMPLES Example 1 Acid Concentrate Formulation

The following amounts of the indicated USP-grade chemicals werecarefully weighed out: 262.0 g sodium chloride (FW 58.45), 9.70 gcalcium chloride (dihydrate, FW 147.02), 3.40 g magnesium chloride(hexahydrate, FW 203.3), 90.0 g dextrose (FW 180.16), 7.0 g citric acid(anhydrous, FW 192.12) and 1.75 g of sodium acetate (trihydrate, FW136.08). The chemicals were placed in a large calibrated beaker and AAMIquality water was added to the 900 ml mark. The beaker was placed on astirring plate and a stirring bar was used to agitated the chemicals andwater. After approximately 10 minutes of stirring, the chemicals hadcompletely dissolved and the solution was ‘crystal clear.’ The stirringbar was removed and the solution was ‘topped off’ with additional AAMIquality water to the 1 liter mark on the beaker. The stirring bar wasreintroduced and the solution was stirred for another 3 minutes.

Example 2 Hemodialysis

The beaker of solution as prepared in Example 1 was taken to a Freseniushemodialysis machine that was ready for use in testing (bypass) mode. Inthis configuration the machine makes dialysate in the same manner aswhen a patient is undergoing a dialysis treatment. The treated watersupply line was attached to the machine and a container of bicarbonateconcentrate was carefully prepared. All solutions were then attached tothe machine and it was turned on.

The machine was allowed to run for 10 minutes at a dialysate flow rateof 800 ml/min. to ensure the prepared solutions had thoroughly filledtheir appropriate pathways through the machine. Additionally, both themachine's conductivity meter as well as an additional conductivitymonitor that had been attached to the dialysate outflow line weremonitored, with readings found to stay within the acceptable range(between 1310 and 1330 millisiemens). The pH of the machine-mixeddialysate was monitored by sampling the drain tube outflow at severalintervals which averaged 10 minutes apart. The pH was 7.4, which waswithin the target range of 7.3 to 7.5. A sample of the outflow wasanalyzed at the University of Washington Medical Center's laboratory toconfirm that the concentrations in the final dialysate were all withinacceptable ranges for hemodialysis.

Finally, after receiving the appropriate approvals, the dialysateprecursor and the resulting dialysate produced by the hemodialysismachine were repeatedly tested in actual patient treatments duringclinical trials of the new dialysate. Throughout the trials, even withdialysis sessions lasting up to five hours, there were no instances ofpH alarms noted.

Example 3 Dialysate Composition

One liter of dialysate composition, excluding sodium bicarbonate, inmEq/L, contains: sodium, 100.3; chloride, 104.25; calcium, 2.5;potassium, 1.0; magnesium, 0.75; acetate, 0.3; citric acid, 2.4; and, ing/l, dextrose, 2.0. The total chemical composition of this dialysatecomposition (which did not contain sodium bicarbonate) was (in grams):NaCl (5.822); CaCl₂ 2H₂O (0.139); KCl (0.074); MgCl₂ 6H₂O (0.036);NaC₂H₃O₂ (0.039); C₆H₈O₇ (0.155) and C₆H₁₂O₆H₂O (2).

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1.-56. (canceled)
 57. A dry dialysate precursor composition comprising asource of chloride, a source of citrate, a source of a buffering anion,and a source of a physiologically-acceptable cation, wherein upon mixingthe dry dialysate precursor composition with water the chloride ispresent in a concentration ranging from about 1,000 to about 7,000mEq/L, the citrate is present in a concentration ranging form about 20to about 900 mEq/L, and the buffering anion is present in aconcentration ranging from about 0.01 to about 150 mEq/L.
 58. The drydialysate precursor composition of claim 57 wherein the source of thebuffering anion is an acetate salt and/or a lactate salt.
 59. The drydialysate precursor composition of claim 57 wherein, upon mixing the drydialysate precursor composition with water, the citrate is present in aconcentration ranging from about 70 to about 150 mEq/L.
 60. The drydialysate precursor composition of claim 57 wherein, upon mixing the drydialysate precursor composition with water, the buffering anion ispresent in a concentration ranging from about 0.3 to about 125 mEq/L.61. The dry dialysate precursor composition of claim 57 wherein thephysiologically-acceptable cation is selected from a group consisting ofhydrogen, sodium, potassium, calcium, magnesium, and combinationsthereof.
 62. The dry dialysate precursor composition of claim 57 furthercomprising a sugar selected from glucose, a poly(glucose), and fructose,wherein, upon mixing the dialysate precursor composition with water, thesugar is present in a concentration of less than about 2,700 g/L. 63.The dry dialysate precursor composition of claim 57 wherein the sourceof citrate is selected from a group consisting of citric acid, sodiumdihydrogen citrate, disodium hydrogen citrate, trisodium citrate,trisodium citrate dihydrate, potassium dihydrogen citrate, dipotassiumhydrogen citrate, calcium citrate, and magnesium citrate.
 64. The drydialysate precursor composition of claim 57 further comprising iron. 65.The dry dialysate precursor composition of claim 64 wherein the iron ispresent in its ferric form.
 66. The dry dialysate precursor compositionof claim 64 wherein the iron is present in its ferrous form.
 67. The drydialysate precursor composition of claim 64 wherein the iron is an ironcomplex or an iron salt.
 68. The dry dialysate precursor composition ofclaim 67 wherein the iron complex is selected from iron dextran, ironsaccharide, iron gluconate, ferric pyrophosphate or ferric citrate. 69.The dry dialysate precursor composition of claim 67 wherein the ironsalt is an iron salt of citrate.
 70. The dry dialysate precursorcomposition of claim 57 further comprising one or more trace elements.